Solvent-dependent self-discrimination of Bis(2-hydroxyphenyl)diamides

Article abstract of DOI:10.1002/chem.201000321

Solvent-dependent, self-dis-crimination of diamides is described. Mixing a solution of (A)-1a and (S)-1a, which are valine-derived, bis(2-hy-droxyphenyl) diamide-bearing, multiple hydrogen-bonding modules, in di-chloromethane immediately led to the formation of a thick suspension com-prising a 1: 1 heterochiral aggregate of la. The solubility of heterochiral la was substantially lower in halogenated solvents than in ethyl acetate. A perus-al of racemic crystal structures ob-tained from chloroform and ethyl ace-tate revealed a significant difference in the crystal-packing pattern, which is likely to be the basis for the pro-nounced difference in solubility. Specif-ic self-discrimination of la in an en-semble of eight structurally related molecules showcased the specific ag-gregation through the hydrogen-bond-ing network of the bis(2-hydroxyphe-nyl)diamide framework. The low solu-bility of heterochiral la in halogenated solvent was exploited to achieve high stereoselectivity in a catalytic asymmet-ric reaction by using a low enantiomer-ic excess sample of la.

Full text of DOI:10.1002/chem.201000321

DOI: 10.1002/chem.201000321
Solvent-Dependent Self-Discrimination of Bis(2-hydroxyphenyl)diamides
Akinobu Matsuzawa, Akihiro Nojiri, Naoya Kumagai,* and Masakatsu Shibasaki*[a]
Abstract: Solvent-dependent, self-dis-
crimination of diamides is described.
Mixing a solution of (R)-1a and (S)-1a,
which are valine-derived, bis(2-hy-
al of racemic crystal structures ob-
tained from chloroform and ethyl ace-
tate revealed a significant difference in
the crystal-packing pattern, which is
likely to be the basis for the pro-
nounced difference in solubility. Specif-
ic self-discrimination of 1a in an en-
semble of eight structurally related
molecules showcased the specific ag-
gregation through the hydrogen-bond-
ing network of the bis(2-hydroxyphe-
nyl)diamide framework. The low solu-
bility of heterochiral 1a in halogenated
solvent was exploited to achieve high
stereoselectivity in a catalytic asymmet-
ric reaction by using a low enantiomer-
ic excess sample of 1a.
ACHTUNGTRENNUNGdroxyphenyl)diamide-bearing, multiple
hydrogen-bonding modules, in di-
chloromethane immediately led to the
formation of a thick suspension com-
prising a 1:1 heterochiral aggregate of
1a. The solubility of heterochiral 1a
was substantially lower in halogenated
solvents than in ethyl acetate. A perus-
Keywords: aggregation · asymmet-
ric catalysis · chiral resolution · mo-
lecular recognition · self-assembly ·
stacking interactions
Introduction
handedness of a molecule is a prominent factor in molecular
differentiation, as exemplified by enantiomeric self-sorting
(recognizing self)[4] and self-discriminating (recognizing op-
posite handedness) systems.[5] Heterochiral association of
several proteinogenic amino acids has recently been docu-
mented in detail, and the behavior of the system was ration-
alized on the basis of ternary eutectic composition, which
led to significant enantiomeric amplification of solution
enantiomeric excess (ee) from a nearly racemic mixture of
amino acids.[6–10] Sublimation of partially resolved com-
pounds also causes enantiomeric amplification due to the
differential vapor pressure of enantiopure samples and their
mixtures.[11–13] These findings have been used to support a
potential rationale for the evolution of homochirality in a
prebiotic environment and are the subject of growing inter-
est.[8,9,11–13] Herein, we report solvent-dependent self-discrim-
ination of valine-derived bis(2-hydroxyphenyl)diamide 1a,
which harbors multiple hydrogen-bonding modules that ex-
hibit extensive heterochiral aggregation of (R)-1a and (S)-
1a to form a highly insoluble heterochiral precipitate from
an ensemble of eight structurally related amides. X-ray crys-
tallographic analyses provided clues to the origin of the
strict heterochiral aggregation of 1a. The high fidelity of the
heterochiral aggregation allowed the generation of a solu-
tion composed of highly enantioenriched 1a from an initial
sample of 5–10% ee. The use of 1a as a chiral ligand in com-
bination with rare earth metals was exploited to produce a
large, nonlinear effect in catalytic asymmetric reactions.
Since the pioneering work of Cram, Lehn, and Pedersen,
supramolecular chemistry has produced a diverse array of
assembled molecular architectures by harnessing various
noncovalent inter- and intramolecular interactions.[1] Inten-
sive research in this area has enhanced the understanding
and development of molecular recognition and self-assembly
processes, leading to the emergence of systems with func-
tions that are molecular in basis.[2] For controlled integration
of molecular architecture to exert a specific function, molec-
ular recognition capabilities that enable high-fidelity, mole-
cule-selective association from an ensemble of molecules
are key. Nature deploys a number of molecular machineries,
such as DNA, RNA, and proteins, to exert a myriad of func-
tions that are initiated by precise molecular recognition, in-
cluding the element of molecular chirality. Intense efforts to
replicate similar molecular recognition processes in the lab-
oratory have revealed various self-assembly systems.[3] The
[a] A. Matsuzawa, A. Nojiri, N. Kumagai, M. Shibasaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku
Tokyo 113-0033 (Japan)
Fax : (+81)3-5684-5206
E-mail: nkumagai@mol.f.u-tokyo.ac.jp
mshibasa@mol.f.u-tokyo.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000321.
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FULL PAPER
methanol remained homogeneous after 3 h of stirring at
308C (Figure 1b).
To delineate the origin of the preferential heterochiral ag-
gregation of 1a and its solvent-dependency, crystals of 1a
were grown under four different conditions: 1) enantiopure
(S)-1a in dichloromethane, 2) enantiopure (S)-1a in ethyl
acetate/n-pentane, 3) racemic 1a in chloroform, and 4) ra-
AHCTUNGTREGcNNNU emic 1a in ethyl acetate/n-pentane; each crystal was ana-
lyzed by X-ray crystallography. The crystal structures of
enantiopure (S)-1a from the different solvent systems were
not appreciably different.[16] In contrast, a marked difference
in the packing pattern of (S)-1a and (R)-1a molecules was
revealed in racemic crystals grown under the different sol-
vent systems. As illustrated in Figure 2, from a racemic solu-
tion of 1a, centrosymmetric cocrystals composed of (R)-
and (S)-1a in a ratio of 1:1 were formed from either chloro-
form or ethyl acetate/n-pentane, confirming that 1a formed
a racemate. A regular zigzag alternating S/R array associat-
ed through hydrogen bonding was observed in the crystal
structure of the racemate from chloroform (Figure 2a and
b), which laterally associated with each other to form highly
insoluble aggregates.[17] On the other hand, a perusal of the
crystal structure of the racemate from ethyl acetate/n-pen-
tane led to the identification of an alternating SS/RR array
associated by hydrogen bonding (Figure 2c and d). The sig-
nificant difference in the solubility of racemic 1a in chloro-
form or ethyl acetate could be ascribed to the enhanced sta-
bility of the zigzag alternating S/R array formed in chloro-
form over the SS/RR counterpart formed in ethyl acetate/n-
pentane. Amino acid residues are presumably not relevant
to the heterochiral aggregation of 1a in crystallographic
analysis, implying that there is the potential to introduce
specific functionality in this moiety to devise a functional
assembly.
Because the self-discrimination of 1a appeared to origi-
nate from the hydrogen-bonding network connecting the
characteristic bis(2-hydroxyphenyl)diamide framework, we
next directed our attention toward the possibility of induc-
ing the specific aggregation of (S)-1a and (R)-1a in an en-
semble of structurally related molecules 1a–g (Scheme 1).
The monoester analogue 1b, bearing a salicylate moiety in-
stead of salicylamide, did not form an insoluble heterochiral
aggregate of 1b upon mixing (R)-1b and (S)-1b in dichloro-
methane, indicating that the diamide substructure of the a-
amino acid is crucial for the construction of the S/R alternat-
ing array found in the heterochiral aggregate of 1a (Fig-
ure 2a). Therefore, along with (R)-1b and (S)-1b, another
ester analogue (S)-1c, deoxy analogues (S)-1d and (S)-1e,
and analogues (S)-1 f and (S)-1g with an appended methyl-
ene group, were prepared and submitted to the same condi-
tions used for the self-discrimination of 1a in the presence
of the closely related sets of different molecules (Figure 3).
In contrast to the formation of heterochiral aggregation in
the mixed solution of (R)-1a and (S)-1a in dichloromethane,
combinations of either (R)-1a/(S)-1b, (R)-1a/(S)-1c, (R)-1a/
(S)-1d, (R)-1a/(S)-1e, (R)-1a/(S)-1 f, or (R)-1a/(S)-1g under
identical conditions did not form a precipitate, validating
Results and Discussion
We previously revealed that diamide 1a, which has two aryl-
oxide moieties and is prepared from valine through a chro-
matography-free process,[14a] can serve as a chiral ligand
upon complexation with rare earth metals to facilitate asym-
1
metric catalysts.[14] In the H NMR spectrum of enantiopure
(S)-1a, chemical shifts of not only NH and OH protons, but
also aromatic CH protons, varied depending on the concen-
tration of the sample;15] this suggested that extensive inter-
molecular interaction of 1a occurred, probably due to hy-
drogen-bonding interactions. In our continuing efforts to
expand the utility of 1a, we found that mixing a 0.1m solu-
tion of (R)-1a and (S)-1a in dichloromethane immediately
led to the formation of a thick suspension (Figure 1a). The
development of the suspension from a 1:1 mixture of a dilut-
ed solution of (R)-1a and (S)-1a was monitored by using a
turbidity meter, which revealed that the formation of the
suspension was complete within 30 min even at 0.01m.[15]
The isolated insoluble material was a racemate of 1a with a
much higher melting point (1728C) than enantiopure 1a
(123–1248C), suggesting that it was not a conglomerate, but
a racemic compound.[6] Formation of the insoluble hetero-
chiral aggregation was dependent on the solvent used; halo-
genated solvents such as dichloromethane or chloroform im-
mediately produced a suspension (Figure 1a), whereas the
heterochiral solution in tetrahydrofuran, ethyl acetate, or
Figure 1. Solvent-dependent heterochiral aggregation of 1a in a) halogen-
ated solvent (CH2Cl2, CHCl3) and b) in THF, AcOEt, or MeOH.
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M. Shibasaki, N. Kumagai et al.
Figure 2. Partial structure of S/R alternating array of the racemic crystal of 1a obtained from CHCl3 (a and b) and that of SS/RR alternating array of the
racemic crystal of 1a obtained from ethyl acetate/n-pentane (c and d). Side view of the array of each crystal showing hydrogen bond network with
dashed line (a and c). Top view of the array of each crystal (b and d). Carbon: dark gray; hydrogen: light gray; nitrogen: blue; oxygen: red; chlorine:
green. Dotted line represents hydrogen bonds.
Figure 3. Self-discrimination of 1a in an ensemble of eight structurally re-
lated molecules.
chloromethane—to develop an ensemble of eight molecules
in equimolar amounts (Figure 4 blue bars)—the solution
gradually became a thick suspension. After stirring for 48 h
Scheme 1. Structurally related bis(2-hydroxyphenyl)amide entities 1b–g.
at (25Æ1)8C, the suspension was filtered off and the filtered
the specific association of (R)-1a and (S)-1a.[15] Upon addi-
tion of a 0.1m solution of (R)-1a (500 mL, 50 mmol) in di-
chloromethane to a mixed solution of (S)-1a, (S)-1b, (S)-1c,
(S)-1d, (S)-1e, (S)-1 f, and (S)-1g (49Æ1 mmol each) in di-
insoluble material was analyzed by HPLC.[15] The insoluble
material was comprised of significant amounts of (S)-1a and
(R)-1a in an almost 1:1 ratio, with only trace amounts of
other species, indicating a high fidelity for the self-discrimi-
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Solvent-Dependent Self-Discrimination
FULL PAPER
strate the large nonlinear effect in catalytic asymmetric reac-
tions.[19] Both 1a and salicyl ester analogue 1b served as
suitable ligands in combination with ScACTHNUTRGEN(UNG OiPr)3 in a catalytic
asymmetric Mannich-type reaction[20] of 2-cyanocyclopenta-
none (2) and N-Boc imine 3 in dichloromethane, to afford
the corresponding product 4 with high anti-selectivity and ee
value (Table 1).[14d] Self-discrimination/enantiomeric amplifi-
Table 1.
Figure 4. Comparison of the amount of each molecule in the ensemble
before and after the self-discrimination. Blue: initial amount of each mol-
ecule. Red: amount of each molecule after self-discrimination of (R)-1a
and (S)-1a from the ensemble of 8 molecules.
Entry
Ligand
Yield [%]
anti/syn
ee [%]
1
2
(S)-1a
(S)-1b
90
93
94:6
89:11
94
93
nation of 1a (Figure 4, red bars).[18] The fact that (R)-1a did
not form an aggregation with either (S)-1 f or (S)-1g provid-
ed further evidence that both the diamide substructure and
the location of the aryloxide functionalities were the domi-
nant factors involved in the heterochiral aggregation.
cation in solution and a large nonlinear effect were antici-
pated for the Mannich-type reaction with a low ee sample of
1a, whereas a low ee sample of 1b was anticipated to give a
nearly racemic product. When a sample of (S)-1a with
10% ee was stirred in dichloromethane/n-hexane for 30 min,
a thick suspension developed. Subsequent addition of Sc-
The 1:1 heterochiral aggregation of 1a, with much lower
solubility than that of enantiopure 1a in halogenated sol-
vents, produced a strong asymmetric amplification of the so-
lution ee value from an initial sample of 1a with low ee
value.[19] Whereas a heterochiral mixture of 1a in ethyl ace-
tate, which was prepared by mixing 0.1m (R)- and (S)-1a so-
lution in ethyl acetate, never formed a suspension, an identi-
cal mixture in dichloromethane rapidly formed a precipitate
of heterochiral aggregate and the ee value of 1a remaining
in the solution was substantially amplified (Figure 5).[15]
From an initial ee value of 4.0%, a dichloromethane/n-
hexane binary solvent system enhanced the solubility ratio
([racemic 1a]/[enantiopure 1a]) and the solution ee value
reached 91.2% after 30 min of stirring at room temperature.
Because 1a enables asymmetric catalysts upon complexa-
tion with rare earth metals,[14] we then proceeded to demon-
A
anti/syn ratio of 93:7, and 91% ee (anti); the reaction thus
exhibited a stereoselectivity comparable to that obtained
from enantiopure (S)-1a (Scheme 2a vs. Table 1, entry 1).
On the other hand, the heterochiral aggregation of the ester
analogue 1b did not occur with a 10% ee heterochiral mix-
ture of (S)-1b in dichloromethane/n-hexane, and a subse-
quent Mannich-type reaction gave nearly racemic
4
(Scheme 2 b vs. Table 1, entry 2). Enantiomeric amplifica-
tion of 1a enabled other catalytic asymmetric reactions to
be performed from a low ee value sample of 1a after filtra-
tion of heterochiral aggregates and solvent exchange. The
diastereoselectivity was switched in the Mannich-type reac-
tion of the same set of substrates in combination with 1a
and Er
vent exchange of the 10% ee sample of 1a in dichlorome-
thane/n-hexane, followed by the addition of Er(OiPr)3, 2,
(OiPr)3 in ether solvent.[14d] Thus, filtration and sol-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
and 3, afforded syn-4 in excellent yield and stereoselectivity
(Scheme 3a). A similar procedure could be applied to the
catalytic asymmetric amination[21] of a-ethoxycarbonyl
amide 5 with di-tert-butyl azodicarboxylate, which was pro-
moted by a ternary catalytic system of LaACTHNUGTRNEUNG(NO3)3·6H2O, 1a,
and H-l-Val-OtBu,[14e] providing the corresponding amina-
tion product with a tetrasubstituted carbon in optically pure
form from a 5% ee sample of 1a (Scheme 3b).
Conclusion
We have studied the heterochiral aggregation of 1a, which
was developed as an effective amide-based chiral ligand in
asymmetric catalysis. The solubility of heterochiral 1a was
Figure 5. Plot of solution ee of 1a versus initial heterochiral mixture of
~
*
^
1a in CH2Cl2 ( ), CH2Cl2/n-hexane ( ), and AcOEt ( ).
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M. Shibasaki, N. Kumagai et al.
Experimental Section
General procedure: Formation of the
heterochiral aggregate and catalytic
asymmetric reactions were performed
in a 20 mL test tube with a Teflon-
coated magnetic stirring bar. The test
tubes were capped with a glass stopper
for the formation of the heterochiral
aggregation under ambient atmos-
phere. The test tubes were fitted with
a three-way glass stopcock for asym-
metric reactions under Ar atmosphere.
All work-up and purification proce-
dures were carried out with reagent-
Scheme 2. Catalytic asymmetric Mannich-type reaction with a low ee sample of 1a or 1b.
grade
solvents
under
ambient
atmosphere.
Heterochiral aggregation of 1a in CH2Cl2: A solution of (R)-1a (0.1m,
1.0 mL, 0.10 mmol) in CH2Cl2 at 308C was added to a stirred solution of
(S)-1a (32.8 mg, 0.10 mmol) in CH2Cl2 (0.1m, 1.0 mL) in a 20 mL test
tube. The resulting mixture immediately developed into a white suspen-
sion. The suspension was stirred at the same temperature for 30 min,
then filtered through filter paper under reduced pressure and the insolu-
ble solid material was washed with a small portion of CH2Cl2. The solid
was dissolved in MeOH and submitted to HPLC analysis [Daicel CHIR-
ALPAK AS-H column; 0.46ꢁ25 cm; eluent: n-hexane/2-propanol=9:1;
flow rate: 1.0 mLminÀ1; detection at 254 nm; tR =8.1 min for (S)-1a, tR =
17.9 min for (R)-1a]. The peak areas for (S)-1a and (R)-1a were identi-
cal, indicating that the insoluble solid was a 1:1 heterochiral mixture,
which was revealed to be a racemate (contains both S and R compounds
in a unit cell) by single-crystal X-ray crystallography. The filtered solid
material was dried under vacuum for 5 h. The melting point (1728C) was
significantly higher than that of enantiopure 1a (123–1248C).
Self-discrimination of (S)-1a and (R)-1a in an ensemble of eight structur-
ally related compounds in CH2Cl2: A test tube was charged with a solu-
tion containing
a mixture of seven compounds (S)-1a–g in THF
[2.65 mL, containing (S)-1a (50 mmol), (S)-1b (50 mmol), (S)-1c
(50 mmol), (S)-1d (48 mmol), (S)-1e (49 mmol), (S)-1 f (50 mmol), and (S)-
1g (49 mmol)]; the concentration was determined by HPLC analysis with
N-methylbenzamide as an internal standard. THF was removed under re-
duced pressure and the resulting residue was dried in vacuo for 30 min.
Anhydrous CH2Cl2 (1000 mL) was added and the Teflon-coated magnetic
stirring bar was placed into the test tube to give a solution of seven com-
pounds in CH2Cl2. The test tube was immersed in an electronically con-
trolled oil bath set at (25Æ1)8C with gentle stirring and a solution of
(R)-1a (0.1m, 500 mL, 50 mmol) in CH2Cl2was added to the stirred solu-
tion. A suspension gradually formed and the resulting suspension was
stirred at the same temperature for 48 h. The suspension was filtered
through a membrane filter with a syringe to give a filtrate sample. The
test tube was rinsed with cooled (À788C) CH2Cl2 (1 mL) and the washing
was filtered through the same membrane filter to collect all the insoluble
material. The membrane filter was washed with cooled (À788C) CH2Cl2
(1 mL). Insoluble material in the membrane filter was eluted with THF
(5 mL at RT, then 5 mL at 458C) to give an aggregate sample. The fil-
trate (100 mL aliquot was taken and submitted to HPLC analysis) and
the aggregate samples were individually analyzed by HPLC with N-meth-
ylbenzamide (500 mL, concentration: 100 mg in 25 mL 2-propanol (IPA))
as an internal standard [Daicel CHIRALPAK IC column; 0.46ꢁ25 cm;
Scheme 3. a) syn-Selective catalytic asymmetric Mannich-type reaction
and b) catalytic asymmetric amination using a low ee sample of 1a.
substantially lower in halogenated solvents compared with
the high solubility in ethyl acetate. A perusal of racemic
crystal structures obtained from chloroform and ethyl ace-
tate revealed a significant difference in the crystal-packing
pattern, which is likely to be the basis for the pronounced
difference in solubility. Specific self-discrimination of 1a in
the ensemble of eight structurally related molecules show-
cased the specific aggregation through the hydrogen-bond-
ing network of the bis(2-hydroxyphenyl)diamide framework.
The low solubility of heterochiral 1a in halogenated solvent
was exploited to achieve high stereoselectivity in catalytic
asymmetric reactions by using a low ee sample of 1a. Future
work will be dedicated to the introduction of functionalities
to the amino acid components of the bis(2-hydroxyphenyl)-
diamide framework, with the aim of developing a functional
assembly.
eluent: n-hexane/MeOH=60:1; flow rate: 1.0 mLminÀ1
; detection:
254 nm]. Retention times and calibration curves for the determination of
the concentration of each compound are summarized in the Supporting
Information.
anti-Selective catalytic asymmetric Mannich-type reaction with a 10% ee
sample of 1a in CH2Cl2/n-hexane: Compounds (S)-1a in CH2Cl2
(1130 mL, 0.11 mmol, 0.976m), (R)-1a in CH2Cl2 (940 mL, 0.090 mmol,
0.961m), and anhydrous n-hexane (3.0 mL) were successively added, by
using a syringe equipped with a stainless-steel needle at RT under an Ar
atmosphere, to a flame-dried 20 mL test tube containing a Teflon-coated
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Solvent-Dependent Self-Discrimination
FULL PAPER
magnetic stirring bar, giving a 10% ee mixture of 1a (excess in S form).
After stirring the resulting suspension at the same temperature for
30 min (heterochiral aggregation of 1a occurred to give a white suspen-
sion), the test tube was immersed in an electronically controlled cooling
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bath at À208C with 2-propanol as medium. Then, Sc
ACHTUNGTRENNUNG
5.0 mmol, 0.2m in n-hexane), (21 mL, 0.2 mmol), and
2
3
0.24 mmol) at À208C were added to the resulting suspension. After stir-
ring at the same temperature for 20 h, 1n aqueous HCl (1 mL) was
added and the resulting mixture was extracted with diethyl ether. The
combined organic layers were washed with a saturated aqueous solution
of NaHCO3 and brine, and then dried over Na2SO4. After filtration, the
organic solvent was removed under reduced pressure and the resulting
residue was submitted to 1H NMR spectroscopic analysis to determine
the diastereomeric ratio [anti/syn=93:7; integrated value of the peaks at
[5] For examples of heterochiral association of metal complexes, see:
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À
À
d=4.98 ppm (syn:
CH(Ph)NHBoc) and d=5.10 ppm (anti:
CH(Ph)NHBoc)]. The crude mixture was purified by silica gel column
chromatography (n-hexane/acetone=10:1) to give Mannich product 4
(58.4 mg, 1.86 mmol, 93% yield). The ee value was determined by HPLC
analysis [Daicel CHIRALPAK IC column; 0.46ꢁ25 cm; eluent: n-
[6] a) S. Eliel, S. H. Wilen, L. N. Mander, Stereochemistry of Organic
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Wilen, Enantiomers, Racemates, and Resolutions, Krieger Publishing,
Malabar, 1994.
hexane/2-propanol=9:1; detection at 254 nm; flow rate: 1.0 mLminÀ1
tR =21.8 min (major), 26.8 min (minor); 91% ee].
;
[7] For recent reviews on enantioenrichment by crystallization, see:
a) R. M. Kellogg, Angew. Chem. 2007, 119, 498; Angew. Chem. Int.
Ed. 2007, 46, 494; b) Y. Wang, A. M. Chen, Org. Process Res. Dev.
2008, 12, 282.
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Financial support was provided from a Grant-in-Aid for Scientific Re-
search on Innovative Areas (N.K.) from MEXT. We are grateful to Dr.
Motoo Shiro at Rigaku Corporation for assistance in X-ray crystallo-
graphic analysis. Dr. A. Tsuchiya is gratefully acknowledged for fruitful
discussions.
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[15] See the Supporting Information and Experimental Section for de-
tails.
[16] CCDC-752886 (rac-1a from CHCl3) and 752887 (rac-1a from
AcOEt/n-pentane) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. Summary of crystallographic analysis and crystal
structures of optically pure 1a from CH2Cl2 and AcOEt/n-pentane
are provided in the Supporting Information.
[17] In reference [8b], the authors provided a crystal structure of racemic
proline incorporating a CHCl3 molecule and proposed that this in-
corporation caused a significant enhancement of the eutectic ee
value. For a more detailed study on the tuning of eutectic composi-
tion by achiral additives, see reference [8e].
[18] The amount of (S)-1b, (S)-1c, (S)-1d, (S)-1e, (S)-1 f, and (S)-1g in
the filtrate remained almost identical to the initial concentration,
whereas the amount of (S)-1a and (R)-1a was significantly de-
creased. A small imbalance of the amount of (S)-1a and (R)-1a in
the filtered insoluble material indicated that tiny amounts of (R)-1a/
(S)-1b–g aggregates were formed.
Received: February 5, 2010
Published online: April 6, 2010
Please note: Minor changes have been made to this manuscript since its
publication in Chemistry–A European Journal Early View. The Editor.
5042
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Chem. Eur. J. 2010, 16, 5036 – 5042